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Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer

Oncogene volume 35, pages 2186–2196 (2016)Cite this article

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Abstract

In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer.

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Acknowledgements

This work was funded by the G. Harold and Leila Y. Mathers Charitable Foundation. This work was supported by NIH grants U54CA151668, P50 CA083639, P50 CA098258 and by the RGK Foundation and the Gilder Foundation.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA

    Z Timsah, Z Ahmed & J E Ladbury

  2. School of Molecular and Cellular Biology, University of Leeds, Leeds, UK

    Z Timsah, J Berrout & J E Ladbury

  3. Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX, USA

    Z Ahmed & J E Ladbury

  4. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Ivan, G N A Pena, G Lopez-Berestein & A K Sood

  5. Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Ivan, G Lopez-Berestein & A K Sood

  6. Department of Molecular and Cellular Biology, Stem Cells and Regenerative Medicine Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    J Berrout

  7. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Unit 63, Houston, TX, USA

    M Gagea & C Vallien

  8. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Medical School, Houston, TX, USA

    Y Zhou & J F Hancock

  9. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Hu

  10. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Unit 1472, Houston, TX, USA

    C V Kingsley

  11. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Lu & G B Mills

  12. Department of Pathology/Laboratory Medicine, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Liu

  13. Department of Genetics, The University of Texas MD Anderson Cancer Center, Unit 1010, Houston, TX, USA

    A B Gladden

  14. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Lopez-Berestein

  15. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M-C Hung

  16. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A K Sood

  17. Department Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Medical School, Houston, TX, USA

    M Bogdanov

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  1. Z Timsah
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  20. J E Ladbury
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Correspondence to J E Ladbury.

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Timsah, Z., Ahmed, Z., Ivan, C. et al. Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer. Oncogene 35, 2186–2196 (2016). https://doi.org/10.1038/onc.2015.279

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  • DOI: https://doi.org/10.1038/onc.2015.279

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